TTFields With Chemotherapy Under Investigation in Locally Advanced Pancreatic Cancer

Teresa Macarulla, MD, PhD

Tumor treating fields (TTFields) concomitant with gemcitabine and nab-paclitaxel (Abraxane) is being compared with chemotherapy alone in the frontline treatment of patients with aggressive, locally advanced pancreatic cancer as part of the phase 3 PANOVA-3 trial (NCT03377491).¹

TTFields are electric fields that apply physical forces to eliminate tumor cells through several mechanisms.² In preclinical models, TTFields has been shown to have enhanced effects spanning solid tumor types when paired with chemotherapy, radiotherapy, immune checkpoint inhibitors, or PARP inhibitors.²

Previously reported data from the phase 2 PANOVA trial (NCT01971281) showed that TTFields concomitant with gemcitabine and nab-paclitaxel had preliminary evidence of clinical benefit in patients with advanced pancreatic adenocarcinoma.¹

Specifically, this approach resulted in a median progression-free survival (PFS) of 12.7 months and a median overall survival (OS) that was not reached (NR) in the intent-to-treat population. In patients with locally advanced disease, the median PFS and OS were both NR. In those with metastatic disease, the median PFS was 9.3 months, and the median OS was NR.¹ Half of the patients experienced treatment-related skin toxicity, with 2 patients experiencing grade 3 dermatitis. No TTFields-related toxicities were determined to be serious.

“[PANOVA-3] is based on a previous phase 2 clinical trial that demonstrated promising activity with a combination of TTFields [and gemcitabine/nab-paclitaxel],” Teresa Macarulla, MD, PhD, a medical oncologist at the Vall d’Hebron University Hospital in Barcelona, Spain, and an investigator on PANOVA-3, said in an interview with OncLive^®. “In theory, with this approach, we try to change the microenvironment of the tumor to help the chemotherapy be [more] active.”

The existing standard-of-care (SOC) treatments for locally advanced pancreatic cancer, including FOLFIRINOX or gemcitabine-based therapy, provide limited efficacy, are linked with moderate-to-high systemic toxicities, and could hinder quality of life (QOL).

PANOVA-3 is a prospective, randomized, multinational, phase 3 study is enrolling patients aged 18 years or older with a histological/cytological diagnosis of de novo unresectable, locally advanced, and nonmetastatic pancreatic adenocarcinoma and who have a life expectancy of at least 3 months and an ECOG performance status of 0 to 2.

Key exclusion criteria include prior palliative treatment to the tumor, other cancers requiring antitumor treatment within 5 years of study inclusion, significant comorbidities, concurrent antitumor therapy beyond gemcitabine and nab-paclitaxel, known severe allergies to medical adhesives, hydrogel, or prescribed chemotherapies, or patients who are pregnant or breast feeding.

Patients will be randomly assigned in a 1:1 fashion to receive TTFields therapy, delivered with the NovoTTF-200T System, at 150kHz frequency for at least 18 hours per day with gemcitabine at 1000 mg/m2 and nab-paclitaxel at 125 mg/m2 on days 1, 8, and 15 of each 28-day cycle, or the same regimen of gemcitabine and nab-paclitaxel alone. Treatment will continue until local disease progression.

Follow-up will occur every 4 weeks, and a computed tomography scan will be conducted every 8 weeks until local disease progression per RECIST v1.1 criteria. Survival follow-up will continue every 4 weeks until death.

OS is the primary end point of PANOVA-3. Secondary end points include local PFS, QOL, pain-free survival, puncture-free survival, objective response rate, 1-year OS rate, resectability rate, and toxicity.

“[Locally advanced pancreatic cancer] is a disease with no positive clinical trials,” Macarulla said. “However, if PANOVA-3 is a positive trial, we will change our SOC, and [we] will treat our patients with TTFields plus chemotherapy. It could be an important step forward for this patient population.”

On February 15, 2023, Novocure announced that the final patient had been enrolled in PANOVA-3.3 After the conclusion of enrollment, an independent data monitoring committee will conduct a prespecified interim analysis pursuant to the trial protocol. Patients will be followed for a minimum of 18 months.

“The next step after this phase 3 trial [will be] to try new combination of strategies [with TTFields],” Macarulla concluded. “It seems that TTFields can change the [tumor] microenvironment. Therefore, a cold tumor may become a hot tumor. Maybe with this approach, we can have better results of immunotherapy in pancreatic cancer.”

References

1. Picozzi VJ, Macarulla T, Philip PA, et al. Tumor treating fields (TTFields) concomitant with gemcitabine and nab-paclitaxel (GnP) for front-line treatment of locally advanced pancreatic cancer: The phase 3 PANOVA-3 study. J Clin Oncol. 2023;41(suppl 4):TPS770. doi:10.1200/JCO.2023.41.3_suppl.TPS770
2. Rivera F, Benavides M, Gallego J, Guillen-Ponce C, Lopez-Martin J, Küng M. Tumor treating fields in combination with gemcitabine or gemcitabine plus nab-paclitaxel in pancreatic cancer: Results of the PANOVA phase 2 study. Pancreatology. 2019;19(1):64-72. doi:10.1016/j.pan.2018.10.004
3. Novocure announces last patient enrolled in pivotal PANOVA-3 study of tumor treating fields in pancreatic cancer. News release. Novocure. February 15, 2023. Accessed February 15, 2023. https://www.novocure.com/